Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D213/62—Oxygen or sulfur atoms
  • C07D213/70—Sulfur atoms
  • C07D213/71—Sulfur atoms to which a second hetero atom is attached
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/16—Amides, e.g. hydroxamic acids
  • A61K31/18—Sulfonamides
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4406—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 3, e.g. zimeldine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/02—Antineoplastic agents specific for leukemia

Definitions

• the present invention relates to novel pyridylsulfonamide derivatives, to a process for their manufacture, pharmaceutical compositions containing them and their manufacture as well as the use of these compounds as pharmaceutically active agents.
• tumor inhibitors are due to a very wide variety of mechanisms, only some of which are known. It is not unusual for known tumor drugs to be found to have new mechanisms of action. This is also to be expected in the case of the compounds according to the invention. Many tumor drugs act by way of mechanisms such as blockading the mechanism of cell division in the cell, preventing the tumor from being supplied with nutrients and oxygen (antiangiogenesis), preventing metastasis, preventing the reception and the onward transmission of growth signals to the tumor cell or forcing the tumor cell into programmed cell death (apoptosis).
• the clinically relevant cytostatic agents are frequently administered in combination in order to achieve a synergistic therapeutic effect.
• WO 2003/035629 relates to thiophene- and thiazolesulfonamides as antineoplastic agents.
• WO 02/098848 and WO 2004/048329 relate to benzoylsulfonamides as antitumor agents. Summary of the invention
• the present invention relates to pyridylsulfonamides of the general formula I
• R 1 is pyridyl which is optionally substituted one to three times by a)-O-phenyl, wherein the phenyl is one or two times substituted by halogen, cyano, alkyl, alkoxy, nitro, amino, alkylamino or dialkylamino; b) -NRR', wherein R and R' independently represent hydrogen or alkyl; or alternatively R and R' form together with the nitrogen atom to which they are attached a saturated 5 to 7 membered heterocycle, which is optionally substituted one to three times by alkyl or alkoxy; c) halogen; or d) alkyl; R 2 is fluorine, chlorine, bromine, methyl, methoxy or trifluoromethyl; R 3 is fluorine, chlorine, bromine, methyl or trifluoromethyl;
• the compounds according to this invention show antiproliferative activity and inhibit the growth of tumor cells in vitro and in vivo.
• Objects of the present invention are the compounds of formula I and their tautomers, pharmaceutically acceptable salts, enantiomeric forms, diastereoisomers and racemates, their use for the inhibition of tumor growth, the preparation of the above-mentioned compounds, medicaments containing them and their manufacture as well as the use of the above-mentioned compounds in the control or prevention of illnesses, especially of cancers such as colorectal, breast, lung, prostate, pancreatic, gastric, bladder, ovarian, melanoma, neuroblastoma, cervical, kidney or renal cancers, leukemias or lymphomas, or in the manufacture of corresponding medicaments.
• cancers such as colorectal, breast, lung, prostate, pancreatic, gastric, bladder, ovarian, melanoma, neuroblastoma, cervical, kidney or renal cancers, leukemias or lymphomas,
• alkyl as used herein means a saturated, straight-chain or branched-chain hydrocarbon containing from 1 to 6, preferably 1 to 4, carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-butyl, t-butyl, n-pentyl, n-hexyl.
• alkoxy as used herein means an alkyl group as defined above which is attached via an oxygen (-O-). Examples include e.g. methoxy, ethoxy, isopropoxy, n-butoxy, 1-methyl-propoxy, 2-methyl-propoxy and the like.
• alkylamino as used herein means an alkyl-NH- group wherein the alkyl is defined as above. Examples include e.g. N-methyl-amino, N-ethyl-amino, N- isopropyl-amino, N-(2-methyl-prop-l-yl)-amino and the like.
• dialkylamino as used herein means an (alkyl) 2 N- group wherein the two alkyl groups are independently defined as above. Examples include e.g. N,N- dimethylamino, N-ethyl-N-methyl-amino, N,N-diethylamino and the like.
• halogen as used herein means fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine or bromine and more preferably chlorine and bromine.
• heterocycle which is formed by R an R' together with the nitrogen atom to which R and R' are attached, means a saturated, monocyclic ring with 5 to 7 ring atoms which contains up to 3, preferably 1 or 2 heteroatoms wherein at least one heteroatom is nitrogen and the remaining heteroatoms are selected independently from nitrogen, oxygen or sulfur, and wherein the remaining ring atoms being carbon atoms.
• saturated heterocycles include pyrrolidine, morpholine, thiomorpholine, piperazine and N-methyl-piperazine, piperidine, oxazolidine, thiazolidine, azepane and the like, preferably morpholine, thiomorpholine, pyrrolidine or azepane, and more preferably morpholine.
• such heterocycles can be optionally substituted one to three times by alkyl or alkoxy.
• such heterocycles can be optionally substituted one to three times by (Ci-C 3 )-alkyl or (Q-C 3 )-alkoxy and more preferably such heterocycles can be optionally substituted once or twice by methyl or methoxy
• pyridyl as used herein means pyrid-2-yl, pyrid-3-yl or pyrid-4-yl, preferably pyrid-2-yl or pyrid-3-yl and more preferably pyrid-3-yl. If such pyridyl is substituted, it is substituted one to three times, preferably one or two times.
• Preferred position of the substituents is ortho to the position of the N-atom of the pyridyl residue, e.g. the 6-position of pyrid-2-yl, the 2- or 6-position, preferably the
• a "pharmaceutically acceptable carrier” is intended to include any and all material compatible with pharmaceutical administration including solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and other materials and compounds compatible with pharmaceutical administration. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the compositions of the invention are contemplated. Supplementary active compounds can also be incorporated into the compositions.
• the term "activated before” means that the carboxylic acid group is converted into a reactive carboxylic acid derivative before the reaction. Such activation is typically carried out without solvent, or in solvents like dichloromethane, dichloroethane, tetrahydrofuran, dioxane and mixtures thereof, at temperatures between O 0 C and 100 0 C. Typical methods used for the activation are chlorination or formation of an imidazolide.
• chlorinating reagents are thionylchloride, oxalyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, N-chlorosuccinamide triphenylphosphine.
• a typically used imidazolination method is the reaction with N,N'-carbonyl diimidazole (CDI).
• Other typically used activation methods include the use of activating agents such as l-ethyl-3-(3'-dimethylaminopropyl)carbodiimide (EDCI), hydroxy-benzotriazole (HOBt) and the like.
• a therapeutically effective amount of a compound means an amount of compound that is effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated. Determination of a therapeutically effective amount is within the skill in the art.
• the therapeutically effective amount or dosage of a compound according to this invention can vary within wide limits and may be determined in a manner known in the art. Such dosage will be adjusted to the individual requirements in each particular case including the specific compound(s) being administered, the route of administration, the condition being treated, as well as the patient being treated. In general, in the case of oral or parenteral administration to adult humans weighing approximately 70 Kg, a daily dosage of about 10 mg to about 10,000 mg, preferably from about 200 mg to about 1,000 mg, should be appropriate, although the upper limit may be exceeded when indicated. The daily dosage can be administered as a single dose or in divided doses, or for parenteral administration, it may be given as continuous infusion.
• ESI+ refers to positive electrospray ionization mode
• One embodiment of the invention are the compounds of formula I, wherein
• R 1 is pyridyl which is optionally substituted one to three times by a)-O-phenyl, wherein the phenyl is one or two times substituted by halogen, cyano, alkyl, alkoxy, nitro, amino, alkylamino or dialkylamino; b) -NRR', wherein R and R' independently represent hydrogen or alkyl; or alternatively R and R' form together with the nitrogen atom to which they are attached a saturated 5 to 7 membered heterocycle, which is optionally substituted one to three times by alkyl; c) halogen; or d) alkyl; and R 2 is fluorine, chlorine, bromine, methyl or trifiuoromethyl.
• R 1 is pyrid-3-yl which is optionally substituted one to three times by a)-O-phenyl; b) -NRR', wherein R and R' form together with the nitrogen atom to which they are attached a saturated 5 to 7 membered heterocycle, which is optionally substituted one to three times by alkyl or alkoxy, preferably by alkyl; or c) halogen.
• R 1 is pyrid-2-yl.
• Another embodiment of the invention are the compounds of formula I, wherein R 1 is pyrid-3-yl.
• Another embodiment of the invention are the compounds of formula I, wherein R 1 is pyrid-4-yl.
• R is pyridyl which is optionally substituted one to three times by a) -NRR', wherein R and R' independently represent hydrogen or alkyl; or alternatively R and R' form together with the nitrogen atom to which they are attached a saturated 5 to 7 membered heterocycle, which is optionally substituted one to three times by alkyl or alkoxy, preferably by alkyl; or b) halogen.
• Another embodiment of the invention are the compounds of formula I, wherein R 1 is pyridyl which is optionally substituted once by
• R and R' independently represent hydrogen or alkyl, preferably alkyl; or alternatively R and R' form together with the nitrogen atom to which they are attached a saturated 5 to 7 membered heterocycle, which is optionally substituted one to three times, preferably once or twice, by alkyl or alkoxy, preferably by alkyl.
• R 1 is pyrid-3-yl which is substituted once by -NRR', wherein R and R' independently represent alkyl; or alternatively R and R' form together with the nitrogen atom to which they are attached a saturated 5 to 7 membered heterocycle, which is optionally substituted once or twice by alkyl or alkoxy.
• Another embodiment of the invention are the compounds of formula I, wherein R 1 is pyridyl which is optionally substituted one to three times by
• R and R' form together with the nitrogen atom to which they are attached a saturated 5 to 7 membered heterocycle, which is optionally substituted one to three times by alkyl or alkoxy, preferably by alkyl.
• Another embodiment of the invention are the compounds of formula I, wherein R 1 is pyrid-3-yl which is substituted once by
• R and R' form together with the nitrogen atom to which they are attached a saturated 5 to 7 membered heterocycle, which is optionally substituted once or twice by alkyl or alkoxy.
• Another embodiment of the invention are the compounds of formula I, wherein R 1 is pyridyl which is optionally substituted one to three times by -O-phenyl.
• R 1 is pyrid-3-yl which is substituted once by
• One embodiment of the invention are the compounds of formula I, wherein R 1 is pyridyl which is optionally substituted one to three times by halogen.
• One embodiment of the invention are the compounds of formula I, wherein R 1 is pyrid-3-yl which is substituted once or twice by halogen.
• Another embodiment of the invention are the compounds of formula I, wherein R 2 is chlorine, bromine, methyl or trifluoromethyl.
• Another embodiment of the invention are the compounds of formula I, wherein R is chlorine, bromine, methyl, methoxy or trifluoromethyl.
• R 3 is chlorine
• Such compounds may be selected from the group consisting of: 6-Morpholin-4-yl-pyridine-3-sulfonic acid 4-chloro-2-fluoro-benzoylamide; sodium salt; and 6-Phenoxy-pyridine-3-sulfonic acid 4-chloro-2-fluoro-benzoylamide; sodium salt.
• R 2 is fluorine; and R is bromine.
• Such compounds may be selected from the group consisting of: 6-Phenoxy-pyridine-3-sulfonic acid 4-bromo-2-fluoro-benzoylamide; sodium salt; 6-Morpholin-4-yl-pyridine-3-sulfonic acid 4-bromo-2-fluoro-benzoylamide; sodium salt; and 5-Bromo-6-chloro-pyridine-3-sulfonic acid 4-bromo-2-fluoro-benzoylamide; sodium salt.
• R 3 is trifluoromethyl.
• Such compounds may be selected from the group consisting of: 6-Morpholin-4-yl-pyridine-3-sulfonic acid 2-fluoro-4-trifluoromethyl- benzoylamide; sodium salt;
• R 3 is chlorine
• Such compounds may be selected from the group consisting of:
• R 3 is fluorine.
• Such compounds may be selected from the group consisting of: 6-Morpholin-4-yl-pyridine-3-sulfonic acid 2-chloro-4-fluoro-benzoylamide; sodium salt;
• R 3 is bromine
• Such compounds may be selected from the group consisting of: 5-Bromo-6-chloro-pyridine-3-sulfonic acid 4-bromo-2-chloro-benzoylamide; sodium salt; and 6-Phenoxy-pyridine-3-sulfonic acid 4-bromo-2-chloro-benzoylamide; sodium salt.
• R 2 is bromine; and R 3 is chlorine.
• Such compounds may be selected from the group consisting of: 5-Bromo-6-chloro-pyridine-3-sulfonic acid 2-bromo-4-chloro-benzoylamide; sodium salt;
• Another embodiment of the invention are the compounds of formula I, wherein R 2 is bromine; and R 3 is fluorine.
• Such compounds may be selected from the group consisting of: Pyridine-3-sulfonic acid 2-bromo-4-fluoro-benzoylamide; sodium salt 6-Morpholin-4-yl-pyridine-3-sulfonic acid 2-bromo-4-fluoro-benzoylamide; sodium salt;
• R 3 is methyl
• Such compounds may be selected from the group consisting of: 6-Morpholin-4-yl-pyridine-3-sulfonic acid 2-bromo-4-methyl-benzoylamide; sodium salt; 5-Bromo-6-chloro-pyridine-3-sulfonic acid 2-bromo-4-methyl-benzoylamide; sodium salt; and 6-Phenoxy-pyridine-3-sulfonic acid 2-bromo-4-methyl-benzoylamide; sodium salt.
• R 2 is methyl; and R 3 is chlorine.
• Such compounds may be selected from the group consisting of: 6-Morpholin-4-yl-pyridine-3-sulfonic acid 4-chloro-2-methyl-benzoylamide; sodium salt;
• 6-Phenoxy-pyridine-3-sulfonic acid 4-chloro-2-methyl-benzoylamide; sodium salt;
• R 2 is methyl; and R 3 is bromine.
• Such compounds may be selected from the group consisting of: 6-Morpholin-4-yl-pyridine-3-sulfonic acid 4-bromo-2-methyl-benzoylamide; sodium salt;
• 5-Bromo-6-chloro-pyridine-3-sulfonic acid 4-bromo-2-methyl-benzoylamide; sodium salt
• 6-Phenoxy-pyridine-3-sulfonic acid 4-bromo-2-methyl-benzoylamide; sodium salt.
• R 3 is methyl
• Such compounds may be selected from the group consisting of: 6-Morpholin-4-yl-pyridine-3-sulfonic acid 2,4-dimethyl-benzoylamide; sodium salt;
• R 2 is trifluoromethyl
• R 3 is fluorine
• Such compounds may be selected from the group consisting of:
• Pyridine-3-sulfonic acid 4-fluoro-2-trifluorornethyl-benzoylamide; sodium salt
• 6-Morpholin-4-yl-pyridine-3-sulfonic acid 4-fluoro-2-trifluoromethyl- benzoylamide; sodium salt
• 6-Phenoxy-pyridine-3-sulfonic acid 4-fluoro-2-trifluoromethyl-benzoylamide; sodium salt;
• R 3 is trifluoromethyl.
• Such compounds may be selected from the group consisting of: S-Bromo- ⁇ -chloro-pyridine-S-sulfonic acid 2,4-bis-trifluoromethyl-benzoylamide; sodium salt;
• R 3 is chlorine
• Such compounds may be selected from the group consisting of:
• 6-Azepan-l-yl-pyridine-3-sulfonic acid 4-chloro-2-trifluoromethyl-benzoylamide; ⁇ -Pyrrolidin-l-yl-pyridine-S-sulfonic acid 4-chloro-2-trifluoromethyl- benzoylamide; ammonium salt;
• 6-Thiomorpholin-4-yl-pyridine-3-sulfonic acid 4-chloro-2-trifluoromethyl- benzoylamide; ammonium salt;
• 6-(Ethyl-methyl-amino)-pyridine-3-sulfonic acid 4-chloro-2-trifluoromethyl- benzoylamide; ammonium salt
• 6-(Methyl-propyl-amino)-pyridine-3-sulfonic acid 4-chloro-2-trifluoromethyl- benzoylamide; ammonium salt
• R 3 is chlorine
• Such compounds may be selected from the group consisting of:
• 6-Thiomorpholin-4-yl-pyridine-3-sulfonic acid 4-chloro-2-methoxy- benzoylamide
• 6-Pyrrolidin-l-yl-pyridine-3-sulfonic acid 4-chloro-2-methoxy-benzoylamide; ammonium salt;
• R 1 is pyrid-2-yl; and R 2 is chlorine, bromine, methyl or trifiuoromethyl.
• R 1 is pyrid-3-yl which is optionally substituted one to three times by a)-O-phenyl; b) -NRR', wherein R and R' form together with the nitrogen atom to which they are attached a saturated 5 to 7 membered heterocycle, which is optionally substituted one to three times by alkyl or alkoxy, preferably by alkyl; or c) halogen; and R 2 is chlorine, bromine, methyl or trifluoromethyl.
• R 2 is trifluoromethyl
• R 3 is fluorine
• R 1 is pyridyl which is optionally substituted one to three times by
• R and R' form together with the nitrogen atom to which they are attached a saturated 5 to 7 membered heterocycle, which is optionally substituted one to three times by alkyl or alkoxy, preferably by alkyl;
• R 2 is chlorine
• R 3 is chlorine
• R 1 is pyrid-3-yl which is optionally substituted one to three times by
• R and R' form together with the nitrogen atom to which they are attached a saturated 5 to 7 membered heterocycle, which is optionally substituted one to three times by alkyl or alkoxy, preferably by alkyl;
• R is chlorine
• R 3 is chlorine
• R 1 is pyrid-3-yl; and R 2 is chlorine, bromine, methyl or trifluoromethyl.
• R 1 is pyrid-3-yl which is substituted one to three times by
• R and R' form together with the nitrogen atom to which they are attached a saturated 5 to 7 membered heterocycle, which is optionally substituted one to three times by alkyl or alkoxy, preferably by alkyl; and R 2 is chlorine, methoxy or trifluoromethyl.
• Another embodiment of the invention are the compounds of formula Ia,
• R and R' independently represent hydrogen or alkyl; preferably alkyl; or alternatively R and R' form together with the nitrogen atom to which they are attached a saturated 5 to 7 membered heterocycle, which is optionally substituted one to three times, preferably once or twice, by alkyl or alkoxy;
• R 2 is fluorine, chlorine, bromine, methyl, methoxy or trifluoromethyl, preferably chlorine, bromine, methyl, methoxy or trifluoromethyl;
• R is fluorine, chlorine, bromine, methyl or trifluoromethyl;
• Another embodiment of the invention are the compounds of formula Ia, wherein
• R and R' independently represent hydrogen or alkyl; preferably alkyl.
• Another embodiment of the invention are the compounds of formula Ia, wherein R and R' form together with the nitrogen atom to which they are attached a saturated 5 to 7 membered heterocycle, which is optionally substituted one to three times, preferably once or twice, by alkyl or alkoxy.
• R and R' form together with the nitrogen atom to which they are attached a saturated 5 to 7 membered heterocycle, which is optionally substituted one to three times, preferably once or twice, by alkyl or alkoxy; and R 2 is chlorine, bromine, methyl, methoxy or trifluoromethyl.
• R and R' form together with the nitrogen atom to which they are attached a saturated 5 to 7 membered heterocycle, which is optionally substituted one to three times, preferably once or twice, by alkyl or alkoxy;
• R 2 is chlorine or trifluoromethyl
• R is fluorine or chlorine.
• the compounds of formula I may be prepared by any process known to be applicable to the preparation of chemically-related compounds. Such preparation is an object of the present invention.
• One embodiment of the invention is a process for the preparation of the compounds of formula I, by reacting a compound of formula III,
• R 1 has the significance given for formula I, with a benzoic acid of formula IV,
• the compounds of formula I, or a pharmaceutically acceptable salt thereof, which are subject of the present invention may be prepared by any process known to be applicable to the preparation of chemically-related compounds. Such processes, when used to prepare a compound of the formula I, or a pharmaceutically-acceptable salt thereof, are illustrated by the following representative schemes 1 and 2 (and the examples) in which, unless otherwise stated, R, R', R 1 , R 2 and R 3 have the significance given herein before. Necessary starting materials are either commercially available or they may be obtained by standard procedures of organic chemistry. The preparation of such starting materials is e.g. described within the accompanying examples or in the literature cited below with respect to schemes 1 and 2. Alternatively necessary starting materials are obtainable by analogous procedures to those illustrated which are within the ordinary skill of an organic chemist.
• the pyridyl-sulfonamide derivatives of formula I can prepared starting e.g. from the corresponding sulfonamide chlorides as shown in scheme 1.
• Step 1 of the reaction sequence (scheme 1) is a one step process in which a pyridine sulfonyl chloride of formula II is converted into a pyridine sulfonamide of formula III using methods well known to someone skilled in the art, e.g. ammonolysis.
• the reaction is typically carried out with or out without solvents such as dichloromethane, dichloroethane, acetonitrile, dioxane, tetrahydrofuran, dimethylformamide and mixtures thereof, at temperatures between -78 0 C and 3O 0 C.
• Pyridine sulfonyl chlorides of formula II are either commercially available or they can be prepared from the corresponding pyridine sulfonic acids by chlorination (see e.g. Corey, E. J.; et al, J. Org. Chem. 54 (1989) 389-393).
• substituted pyridyl-3-sulfonamide derivatives of formula III which are substituted at the 6-position with a nitrogen-containing heterocycles such as morpholine, thiomorpholine, pyrrolidine, piperidine, azepane and the like or with secondary amines such dimethylamino, diethylamine and the like, can be either prepared from 6-chloro-pyridyl-3-sulfonamide (via the 6-chloro- pyridyl-3-sulfonic acid chloride; see e.g. Naegeli, C; et al, Helvetica Chimica Acta
• Step 2 of the reaction sequence is a two step process in which activation of the carboxylic group of the benzoic acid of formula IV is followed by acylation of the sulfonamide of formula III, to give the acylsulfonamide derivatives of formula I, using methods well known to someone skilled in the art.
• the first step (activation) is typically carried out with or without solvents (such as dichloromethane, dichloroethane, tetrahydrofuran, dioxane and mixtures thereof), at temperatures between O 0 C and 100 0 C.
• solvents such as dichloromethane, dichloroethane, tetrahydrofuran, dioxane and mixtures thereof
• chlorinating reagents are thionyl chloride, oxalyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride and N-chlorosuccinimide with triphenylphosphine.
• a typically used imidazolination method is the reaction with N,N'-carbonyl diimidazole (CDI).
• Other typically used activation methods include the use of activating agents such as l-(3-dimethylaminopropyl)-3- ethylcarbodiimide (EDCI) with or without hydroxy-benzotriazole (HOBt) and the like.
• the second step (acylation) is typically carried out in solvents such as dichloromethane, dichloroethane, acetonitrile, dioxane, tetrahydrofi ⁇ ran, chloroform, dimethylformamide and mixtures thereof, at temperatures between - 1O 0 C and 100 0 C.
• solvents such as dichloromethane, dichloroethane, acetonitrile, dioxane, tetrahydrofi ⁇ ran, chloroform, dimethylformamide and mixtures thereof, at temperatures between - 1O 0 C and 100 0 C.
• bases are sodium hydride, potassium hydride, potassium carbonate, triethylamine, diisopropylethylamine, and (1,8- diazabicyclo [5.4.0] undec-7-ene (DBU).
• the substituted pyridyl-3-sulfonamide derivatives of formula I which are substituted at the 6-position of the pyridyl with a nitrogen-containing heterocydes such as morpholine, thiomorpholine, pyrrolidine, piperidine, azepane and the like or with amines such dimethylamine, diethylamine and the like, are named Ia, and can be prepared according to the following scheme 2.
• the compounds of formula Ia in scheme 2 can be prepared via the 6-chloro- pyridyl-3-sulfonamide.
• 6-chloro-pyridyl-3-sulfonamide is either commercially available, or 6-chloro- pyridyl-3-sulfonamide can be prepared from 6-chloro-pyridin-3-ylamine via 6- chloro-pyridyl-3-sulfonic acid chloride following the first two steps of the reaction sequence in scheme 2; or alternatively 6-chloro-pyridyl-3-sulfonamide is prepared according to Naegeli, C; et al, Helvetica Chimica Acta 21 (1938) 1746-1756 or US 3,991,057A.
• 6-chloro-pyridyl-3-sulfonamide is then reacted with the nitrogen-containing heterocycle or amine of formula IV, in the presence of a base like diisopropylethylamine, triethylamine, sodium hydride, potassium hydride, and DBU (l,8-diazabicyclo[5.4.0]undec-7-ene, in solvents such as dichloromethane, acetonitrile, dioxane, tetrahydrofuran, chloroform, dimethylformamide, N- methylpyrrolidone and mixtures thereof, at temperatures between -1O 0 C and 100 0 C, to give the compounds of formula IHa.
• a base like diisopropylethylamine, triethylamine, sodium hydride, potassium hydride, and DBU (l,8-diazabicyclo[5.4.0]undec-7-ene, in solvents such as dichloromethane, aceton
• the sulfonamides of formula IHa are acylated by the benzoic acid chlorides of formula V (obtained from the benzoic acid of formula IV by chlorination- see details under step 2, scheme 1) to give the corresponding pyridyl- 3-sulfonamide derivatives of formula Ia.
• the reaction is typically carried out in solvents such as dichloromethane, dichloroethane, acetonitrile, dioxane, tetrahydrofuran, chloroform, dimethylformamide and mixtures thereof, at temperatures between -1O 0 C and 100 0 C.
• bases are sodium hydride, potassium hydride, potassium carbonate, triethylamine, diisopropylethylamine, and (l,8-diazabicyclo[5.4.0]undec-7-ene (DBU).
• the compounds of formula I can contain one or several chiral centers and can then be present in a racemic, a enantiomeric or diastereomeric form.
• the racemates can be separated according to known methods into the enantiomers. For instance, diastereomeric salts which can be separated by crystallization are formed from the racemic mixtures by reaction with an optically active acid such as e.g. D- or L- camphorsulfonic acid. Alternatively separation of the enantiomers can also be achieved by using chromatography on chiral HPLC-phases which are commercially available.
• composition or medicaments containing a compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier are an object of the present invention, as is a process for their production, which comprises bringing one or more compounds of the present invention and/or pharmaceutically acceptable salts and, if desired, one or more other therapeutically valuable substances into a galenical administration form together with one or more pharmaceutically acceptable carriers.
• An embodiment of the invention is a pharmaceutical composition, containing one or more compounds according to formula I, together with pharmaceutically acceptable carriers.
• Another embodiment of the invention is a pharmaceutical composition, containing one or more compounds according to formula I, for the inhibition of tumor growth.
• Another embodiment of the invention is a pharmaceutical composition, containing one or more compounds according to formula I, for the treatment of cancer.
• Another embodiment of the invention is a pharmaceutical composition containing one or more compounds of formula I as active ingredients together with pharmaceutically acceptable carriers for the treatment of colorectal, breast, lung, prostate, pancreatic, gastric, bladder, ovarian, melanoma, neuroblastoma, cervical, kidney or renal cancers, leukemias or lymphomas.
• Another embodiment of the invention is the use of a compound according to formula I, for the manufacture of corresponding pharmaceutical compositions for the inhibition of tumor growth.
• Another embodiment of the invention is the use of a compound according to formula I, for the manufacture of corresponding pharmaceutical compositions for the treatment of cancer.
• Another embodiment of the invention is the use of the compounds of formula I as anti-proliferating agents.
• Another embodiment of the invention is the use of one or more compounds of formula I for the treatment of cancer.
• the compounds according to the present invention may exist in the form of their pharmaceutically acceptable salts.
• pharmaceutically acceptable salt refers to conventional acid-addition salts that retain the biological effectiveness and properties of the compounds of formula I and are formed from suitable non-toxic organic or inorganic bases or, if the compounds of formula I contain a basic group in R 1 , from organic or inorganic acids.
• base-addition salts include those derived from sodium, potassium, ammonium, quaternary ammonium hydroxides (such as for example, tetramethylammonium hydroxide), especially from sodium.
• acid-addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and those derived from organic acids such as p-toluenesulfonic acid, salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid, and the like.
• the chemical modification of a pharmaceutical compound (i.e. a drug) into a salt is a technique well known to pharmaceutical chemists to obtain improved physical and chemical stability, hygroscopicity, flowability and solubility of compounds. See e.g. Stahl, P. H., and Wermuth, G., (editors), Handbook of Pharmaceutical Salts, Verlag
• the compounds of formula I and their pharmaceutically acceptable salts possess valuable pharmacological properties. It has been found that said compounds show anti-proliferative activity. Consequently the compounds of the present invention are useful in the therapy and/or prevention of proliferative diseases such as cancer.
• the activity of the present compounds as anti-proliferative agents is demonstrated by the following biological assay:
• the CellTiter-GloTM Luminescent Cell Viability Assay (Promega) is a homogeneous method of determining the number of viable cells in culture based on quantitation of the ATP present, which signals the presence of metabolically active cells.
• HCT 116 cells human colon carcinoma , ATCC-No. CCl-247 were cultivated in RPMI 1640 medium with GlutaMAXTM I (Invitrogen, Cat-No. 61870-010), 5 %
• FCS Fetal Calf Serum
• FBS Fetal Calf Serum
• lOOUnits/ml penicillin/lOO ⁇ g/ml streptomycin Pen/Strep from Invitrogen Cat.No. 15140
• the cells were seeded in 384 well plates, 1000 cells per well, in the same medium. The next day the test compounds were added in various concentrations ranging from 30 ⁇ M to 0.0015 ⁇ M (10 concentrations, 1:3 diluted). After 5 days the
• CellTiter-GloTM Luminescent Cell Viability Assay from Promega.
• the cell-plate was equilibrated to room temperature for approximately 30 minutes and than the CellTiter-Glo reagent was added. The contents were carefully mixed for 15 minutes to induce cell lysis. After 45 minutes the luminescent signal was measured in Victor 2, (scanning multiwell spectrophotometer, Wallac). Details: 1st, day:
• the compounds according to this invention and their pharmaceutically acceptable salts can be used as medicaments, e.g. in the form of pharmaceutical compositions.
• the pharmaceutical compositions can be administered orally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions.
• the administration can, however, also be effected rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions.
• compositions can be obtained by processing the compounds according to this invention with pharmaceutically acceptable, inorganic or organic carriers.
• Lactose, corn starch or derivatives thereof, talc, stearic acids or it's salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragees and hard gelatine capsules.
• Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. Depending on the nature of the active substance no carriers are, however, usually required in the case of soft gelatine capsules.
• Suitable carriers for the production of solutions and syrups are, for example, water, polyols, glycerol, vegetable oil and the like.
• Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.
• compositions can, moreover, contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
• compositions comprise e.g. the following:
• 6-Morpholin-4-yl-pyridine-3-sulfonyl chloride (1.25g, 4.8mmol) was dissolved in a
• aqueous eluent is water with 0.2 % acetic acid and the organic eluent is acetonitrile with 0.2 % acetic acid
• tetrahydrofuran e.g. 10 ml
• 1 eq. e.g. 1 mmol
• sodium methoxide 25% solution in methanol
• the tetrahydrofuran is removed in vacuo and the residue suspended in diethyl ether (e.g. 50 to 100 ml) and heated to reflux four 1 hour, cooled down to room temperature filtered off and dried.

Landscapes

• Chemical & Material Sciences (AREA)
• Health & Medical Sciences (AREA)
• Organic Chemistry (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Medicinal Chemistry (AREA)
• Animal Behavior & Ethology (AREA)
• Life Sciences & Earth Sciences (AREA)
• Pharmacology & Pharmacy (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Epidemiology (AREA)
• Oncology (AREA)
• Hematology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Pyridine Compounds (AREA)

Priority Applications (7)

Applications Claiming Priority (2)

Publications (1)

Family

ID=36143754

Family Applications (1)

Country Status (12)

Families Citing this family (4)

Citations (4)

Family Cites Families (4)

• 2006
  • 2006-11-08 US US11/594,297 patent/US7625896B2/en not_active Expired - Fee Related
  • 2006-11-13 BR BRPI0618990-3A patent/BRPI0618990A2/pt not_active IP Right Cessation
  • 2006-11-13 KR KR1020087012217A patent/KR101067313B1/ko not_active IP Right Cessation
  • 2006-11-13 WO PCT/EP2006/010847 patent/WO2007059872A1/en active Application Filing
  • 2006-11-13 JP JP2008540496A patent/JP2009515916A/ja active Pending
  • 2006-11-13 CN CN2006800412842A patent/CN101300231B/zh not_active Expired - Fee Related
  • 2006-11-13 EP EP06829015A patent/EP1960361A1/en not_active Withdrawn
  • 2006-11-13 AU AU2006317179A patent/AU2006317179A1/en not_active Abandoned
  • 2006-11-13 CA CA002629544A patent/CA2629544A1/en not_active Abandoned
  • 2006-11-14 TW TW095142169A patent/TW200736220A/zh unknown
  • 2006-11-23 AR ARP060105171A patent/AR058230A1/es not_active Application Discontinuation
• 2008
  • 2008-03-20 IL IL190334A patent/IL190334A0/en unknown

Patent Citations (4)

Also Published As

Similar Documents

Legal Events